INTENSIFICATION AND DEPLETION OF SPECIFIC BULKY RENAL DNA-ADDUCTS (I-COMPOUNDS) FOLLOWING EXPOSURE OF MALE F344 RATS TO THE RENAL CARCINOGEN FERRIC NITRILOTRIACETATE (FE-NTA)

The effects of the renal carcinogen ferric nitrilotriacetate (Fe-NTA) on kidney DNA of male F344 rats were studied to determine whether bulk y DNA oxidation products (putative intrastrand crosslinks) could be de tected by P-32-postlabeling in the target organ of carcinogenesis. Rat s (10-11 weeks old) were given a single dose of Fe-NTA (15 mg Fe/kg bo dy weight) i.p. at 3:00 pm. After 5 h, renal DNA from Fe-NTA-treated a nd vehicle control animals was assayed by P-32-postlabeling. Thin-laye r chromatography and quantitative analysis of two labeled nucleotide f ractions of increasing polarity, L and C, showed that three spots (L1, L2, and C3) were intensified 3.5- to 4.2-fold in treated animals. L1 consisted of subfractions L1a, L1b, and Lie, which could be resolved c hromatographically. Lie, L2, and C3 were identical to DNA oxidation pr oducts generated by the Fenton reaction in vitro, while L1a and L1b ap parently did not arise by this mechanism. DNA damage and toxicity appe ared reduced in younger animals and animals treated in the morning, pr esumably due to differences in antioxidant defenses. Liver and lung (n on-target organs) DNA did not exhibit enhanced L1, L2, and C3 spots. I n addition to augmenting renal I-compounds, Fe-NTA reduced the levels of three major polar kidney I-compounds (C4, C5, and C6) to 22-53% of control. This reduction did not appear to arise by direct oxidative DN A damage, resembling the previously documented loss of liver I-compoun ds induced by numerous hepatocarcinogens. Two of these I-compounds (C4 and C5) have been reported to exhibit positive linear correlations wi th median lifespan of male F344 rats. The pleiotropic response of kidn ey I-compound levels to Fe-NTA was consistent with different roles of different types (I and II) of I-compounds in Fe-NTA-mediated renal car cinogenesis. The results strongly support a causal relationship betwee n oxidative DNA lesions and Fe-NTA-mediated carcinogenesis.